S-triazolo(5,1-a)isoquinolines and derivatives thereof

ABSTRACT

S-TRIAZOLO(5,1-A)ISOQUINOLINES ARE PREPARED BY CYCLIZATION OF A N-(1-ISOQUINOLYL)AMIDINE, 5,6-DIHYDRO-S-TRIAZOLO (5,1-A)ISOQUINOLINES ARE PREPARED BY REDUCING THE STRIAZOLO(5,1-A)ISOQUINOLINES. THE NOVEL COMPOUNDS OF THE INVENTION ARE USEFUL AS ANTIOXIDANTS, CORROSION INHIBITORS, AS REACTION INTERMEDIATES, AND AS ACID ACCEPTORS.

United States Patent Oflice';

7, 3,758,480 Patented Sept. 11, 1973 3,758,480s-TRIAZOL[5,1-a]ISOQUINOLINES AND DERIVATIVES THEREOF Hans K.Reimlinger, Brussels, and Jan Joseph Maurice Vandewalle, Mortsel,Belgium, assignors to Mallinckrodt Chemical Works, St. Louis, M0. N0Drawing. Filed July 10, 1968, Ser. No. 743,628 Int. Cl. C07d 35/34 US.Cl. 260-288 R 1 Claim ABSTRACT OF THE DISCLOSUREs-Triazolo[5,1-a]isoquinolines are prepared by cyclization of aN-(1-isoquinolyl)amidine. 5,6-dihydro-s-triazolo [5,1-a]isoquinolinesare prepared by reducing the striazolo[5,1-a]isoquinolines. The novelcompounds of the invention are useful as antioxidants, corrosioninhibitors, as reaction intermediates, and as acid acceptors.

The invention relates to s-triazolo[5,1-a]isoquinolines and to5,6dihydro-s-triazolo[5,1-a1isoquinolines. These two classes ofcompounds have the following basic structures:

NUT-R1 I 1i 9 N/ 8 y. 7 6

5,6-dihydro-s-triazolo 5,1-a] lsoquinollnes wherein the R variable is asdefined below.

The s-triazolo[5,1-a1isoquinolines can be produced by the followingsequence of reactions, starting with known types of reactants:

(a) A l-aminoisoquinoline is reacted with a nitrile to produce anN-(1-isoquinolyl)amidine:

(b) The N-(1-isoquinolyl)amidine is then contacted with leadtetraacetate to effect ring closure and thereby produce thes-triazolo[5,1-a1isoquinoline:

Reaction (a) is carried out by reacting a l-aminoisoquinoline with anitrile. Ordinarily, a Lewis acid catalyst is used, although in somecases, no catalyst is needed. The nitriles that are used are compoundsof the formula:

( R -CN wherein R represents alkyl, alkaryl, aralkyl, aryl, haloalkyl,cycloalkyl, heterocyclic groups, alkoxyalkyl groups, and the like.

Specific illustrative nitriles that can be used in the invention includethe following compounds:

acetonitrile, propionitrile, butyronitrile, valeronitrile,hexanenitrile, heptanenitrile, octanenitrile, decanenitrile,dodecanenitrile, tetradecanenitrile, hexadecanenitrile,octadecanenitrile, eicosanenitrile,

and other alkanenitriles having up to 20 carbon atoms. The preferredalkanenitriles are those having up to six carbon atoms, and those havingfrom two to four carbon atoms are more preferred.

Other useful nitriles include the aromatic and cycloalkyl nitriles suchas the following compounds:

benzonitrile,

cyclohexanenitrile,

cyclopentanitrile, p-methylbenzonitrile, phenylacetonitrile (benzylcyanide), a-phenylbutyronitrile,

and the like.

Other useful nitriles include the haloalkyl nitriles such as thefollowing compounds:

chloroacetonitrile, trichloroacetonitrile, trifluoroacetonitrile,fiuoroacetonitrile, fi-chloropropionitrile, p-bromopropionitrile,-chlorobutyronitrile, a-chloroisobutyronitrile,

and the like.

Still other useful nitriles include the heterocyclic nitriles such asthe following compounds:

a-cyanotetrahydrofuran 2-furylacetonitrile, 2-cyanopyridine,N-(fi-cyanoethyDpyrrole,

In reaction (a), the other starting reactant is a l-aminoisoquinoline.These compounds can be obtained by the following types of reactions:

The known reaction of unsubstituted isoquinoline orhydrocarbyl-substituted isoquinolines with sodium 5 amide in liquidammonia:

N NaNH, N 9 liquid NH;

N NaNHg N liquid NHa 843B (d) The known reaction of1,3-dichloroisoquinolines with alcoholic ammonia at 180 0.:

V CI

(e) The known reduction of a l-hydrazinoisoquinoline (prepared byreacting a l-chloroisoquinoline with hydrazine) with hydrogen using apalladium catalyst:

NH; in ethanol NHNH, N H,

N H: N Pd catalyst R R (in the published cases, R was ethyl or butyl,but it can be other alkyl, aryl, or the like).

(f) Reaction of a l-methoxyisoquiuoline with sodium amide and liquidammonia at atmospheric pressure in refluxing toluene:

OCH; NH,

N NaNHz,NH3 N 60 O O Refluxing Toluene l-methoxyisoquinolines areproduced by refluxing 1- chloroisoquinolines with sodium methoxide inmethanol. Under these conditions, chloro substituents on the 4 positiondo not react. By this procedure, 1-amino-4-chloroisoquinolines can beproduced.

(g) 1-amino-4-nitroisoquinolines can be prepared by the conventionalnitration of a l-aminoisoquinoline. The nitro group does not interferewith reactions (a) and (b), and it can be used subsequently forproducing derivatives of s-triazolo-[5,1-a]isoquinolines havingsubstituents in the v6 position. The nitration reaction is exemplifiedby the following:

NH, NH,

N HNO: N

(h) I-aminoisoquinolines having alkoxy substituents in the benzene ringor other easily reducible substituents can be produced by the followingsequence of reactions:

CHa

' IIIHNH; N 0115 CH3O g Acetophenone Onto NH -H;O CH3O CHaO t /N=C IIIsHs CHQO NH Zinc dust in CHBO N acetic acid G CHQO Room temperature CH3OThe foregoing techniques can be used to prepare a wide variety ofl-aminoisoquinolines. Unsubstituted and hydrocarbyl-substitutedl-aminoisoquinolines are readily available via reaction (c).l-aminoisoquinolines containing chloro substituents are readilyavailable via reactions (d) or (f). l-amino-4-nitroisoquinolines can beproduced by reaction (g). l-amino-isoquinolines containing alkoxysubstituents are available through the correspondingl-hydrazinoisoquinolines by reactions (e) and (h). The correspondingl-hydrazinoisoquinolines are readily prepared by the known reaction of al-chloroisoquinoline with hydrazine. Many l-chloroisoquinolines areknown. A useful method for synthesizing l-chloroisoquinolines is toreact an isocarbostyril with phosphorus oxychloride in accordance withthe following reaction:

NH OPCla N I CH3 CH3 t JN ON In preparing a l-hydrazinoisoquinoline froma l-chloroisoquinoline that contains additional chloro substituents, thereaction with hydrazine should be carried out in methanol. Thel-hydrazinoisoquinoline is formed first, and it then precipitates fromsolution thereby avoiding the preparation ofpoly-hydrazinoisoquinolines.

Among the l-aminoisoquinolines that can be used in reaction (a) are thefollowing compounds:

l-aminoisoquinoline, 1-amino-3-chloroisoquinoline, l-amino-4-chloroisoquinoline,

I l-amino-3-methy1isoquinoline,

lyst is required for the reaction, although with some nitrilescontaining fiuoro substituents on the alpha carbon atom, no catalyst isneeded. The Lewis acid catalysts used are compounds such as aluminumtrichloride, titanium tetrachloride, tetraisopropyl titanate, borontrifluoride, and the like. Aluminum trichloride is preferred. Thecatalyst is employed in catalytically effective quantities, such as fromabout to 150 weight percent, and preferably from about 50 to 120 weightpercent, based upon weight of the l-aminoisoquinoline.

With some nitriles having one or more fluoro substituents on the alphacarbon atom, no catalyst is needed. For instance, whentrifluoroacetonitrile is used in reaction (a), no catalyst is required.

The exact temperature to be used in the reaction depends, in part, uponthe nature of the reactants, and particularly upon the nature of thenitrile. For instance, when trifluoroacetonitrile is used in reaction(a), the reaction proceeds at room temperature. With less reactivenitriles, higher temperatures are used. For instance, temperatures offrom about 150 C. to about 210 C. can be used, with temperatures of fromabout 175 to about 200 C. being preferred.

The reaction is conveniently carried out in an inert solvent either byadding catalyst to a solution of nitrile plus l-aminoisoquinoline, or byadding nitrile to a solution of l-aminoisoquinoline (either with orwithout a catalyst). In any event, it is desirable to avoid addingnitrile to catalyst without a l-aminoisoquinoline being present in orderto avoid trimerization of the nitrile to an s-triazine which will reducethe yields of the desired amidine product of reaction (a).

Suitable inert solvents include hydrocarbons such as benzene, toluene,xylene, naphthalene, methylnaphthalene and the like.

The proportions of the reactants are not narrowly critical. Aboutstoichiometric proportions can be used, although higher yields areobtained in most cases when excess nitrile is employed. It is thereforedesirable to employ up to about 150 percent molar excess of nitrile.

The reaction can be carried out in conventional equipment at atmosphericpressure, or under super-atmospheric pressure in the event that thereaction is to be carried out at a temperature exceeding the boilingpoint of any of the reactants or solvent. In such cases, the reaction ispreferably carried out in a closed vessel under autogenous pressure.

Reaction (a) is carried out for a period of time sufi'icient to producean N-(l-isoquinolyl)amidine. The exact time selected will vary, to anextent, with the reaction temperature and the nature of the amidine.Usually, the higher temperature reactions are faster, for instance, fromabout /z to about 5 hours, and preferably from about 2 to about 3 hours.The reactions that are carried out at low temperatures, e.g., thosewherein the nitrile is activated by fiuoro substituents or the alphacarbon atom, normally are slower. For instance, reaction times of up to100 hours, and preferably from about 25 to about 80 hours, can beemployed.

The amidine product is recovered by conventional procedures. Forinstance, the reaction mixture containing catalyst, product, andunreacted starting material can be poured into aqueous acid (such ashydrochloric acid) to form a water-soluble amidine salt. The solvent canthen be decanted, after which the aqueous mixture can be cooled andalkali added to precipitate the organic materials (i.e., product andunreacted starting material). The crude amidine can then be purified bydissolving it in diethyl ether, drying the ethereal solution, andevaporating the ether. The amidine can be further purified by dissolvingit in benzene and passing the benzene solution through a neutralaluminum oxide column. The unreacted starting material is adsorbed inthe column, and the pure amidine is recovered by evaporating thebenzene.

In cases where no Lewis acid catalyst is used, it is not necessary touse water extraction. In many cases, the amidine can be recovered simplyby evaporating the solvent. In some cases, it may also be desirable topass a solution of the amidine through a neutral aluminum oxide columnin order to remove unreacted starting material.

In the second step for producing the s-triazolo[5,1-a] isoquinolines ofthe invention, i.e., reaction (b), the amidine product of reaction (a)is contacted with lead tetraacetate to effect ring closure and therebyproduce an s-triazolo[5,l-a]isoquinoline. This reaction is carried outsimply by heating a mixture of the amidine and lead tetraacetate in asuitable solvent for a period of time suflicient to effect ring closure.The temperature can vary from about 75 C. to about C. The reaction timewill vary depending on the temperature, nature of the amidine, and thelike, but in general will be from about 10 minutes to about 45 minutes.

A convenient way to carry out reaction (b) is to reflux a mixture ofamidine and dry lead tetraacetate in a solvent having a suitable boilingpoint. Such solvents include benzene, toluene, xylene, cyclohexane,glacial acetic acid, or mixtures thereof.

The lead tetraacetate is preferably used in at least stoichiometricproportions. For instance, from about 1.1 to about 2 moles of leadtetraacetate per mole of amidine is suitable in most cases.

The s-triazolo[5,1-a]isoquinoline product of reaction (b) can berecovered by conventional procedures. For instance, the cooled reactionmixture can be washed with aqueous alkali, and the product can beseparated from the basic aqueous mixture as a solution in a hydrocarbonsolvent such as benzene. After drying, the solvent can be removed byevaporation to yield the product. Further purification byrecrystallization can be performed if desired.

Among the s-triazolo[5,1-a]isoquinolines that can be produced, by thesequence of reactions (a) and (b) described above, from known and/orreadily available nitriles and l-aminoisoquinolines, are the followingspecific illustrative compounds:

Z-methyl-s-triazolo 5, 1-a]isoquinoline, Z-ethyI-s-triazolo [5 l-a]isoquinoline, 2-propyl-s-triazolo [5 l-a] isoquinoline,2-butyl-s-triazolo [5, 1-a]isoquinoline, 2-pentyl-s-triazolo 5 l-a]isoquinoline, 5-chloro-2-methyl-s-triazolo [5 l-a] isoquinoline,6-chloro-Z-methyl-s-triazolo [5 l-a] isoquinoline,

2,5 -dimethyl-s-triazolo [5 l-a] isoquinoline,2,S-dimethyl-6-cyano-s-triazolo[5,1-a1isoquinoline,9-ch1oro-2-methyl-s-triazolo 5, 1-a]isoquinoline,2-ethyl6-nitro-s-triazolo 5 1a] isoquinoline,6-ethoxy-2-methyl-s-triazolo [5 l-a] isoquinoline,6-butoxy-2-hexyl-s-triazolo [5 l-a] isoquinoline,7-methoxy-2-methyls-triazolo [5 l-a] isoquinoline,8-methoxy-2-methyl-s-triazolo [5, l-a] isoquinoline,9-methoxy-Z-methyl-s-triazolo [5 l-a] isoquinoline,8,9-dimethoxy-2-methyl-striazolo [5, l-a] isoquinoline, 7,8,9-trimethoxy-Z-methyl-s-triazolo [5 1-a]isoquinoline,

and other 2-alkyl-s-triazo1o [5, 1-a]isoquino1ines.

Other illustrative compounds include:

Z-phenyl-s-triazolo [5, l-a] isoquinoline, 2-cyclohexyl-s-triazolo [5l-a] isoquinoline, 2-cyclopentyl-s-triazolo 5, l-a] isoquinoline,2-tolyl-s-triazolo [5,1-a1isoquinoline, 2-phenylmethyl-s-triazolo 5 l-a]isoquinoline, S-chloro-2-phenyl-s-triazolo [5 l-a] isoquinoline,6-chloro-2-phenyl-s-triazolo [5 1 -a] isoquinoline,8-methoxy-2-phenyl-s-triazolo [5 l-a] isoquinoline,

and other 2-aryl-, 2-cycloalkyl-, 2-alkaryl-, andZ-aralkyls-triazolo[5,l-a1isoquinolines.

Additional specific illustrative compounds include:

2-trifiuoromethyl-s-triazo1o 5, 1-a]isoquinolines,

2-chloromethyl-s-triazolo [5, l-a] isoquinoline,

2-trichloromethyl-s-triazolo [5 l-a] isoquinoline,

2-flu0romethyl-s-triazolo [5,1-a] isoquinoline,

2-(beta-chloroethyl)-s-triazolo[5,1-a]isoquinoline,

2- gamma-chloropropyl -s-triazo1o [5, l-a] isoquinoline,

7,8,9-trirnethoxy-Z-trifluoromethyl-s-triazolo 5, l-a] isoquinoline,

6-nitro-Z-trifluoromethyl-s-triazolo [5 1-a]iso quinoline,

and other 2-haloalkyl-s-triazolo 5, l-a] isoquinolines.

Further illustrative compounds include:

2-methoxymethyl-s-triazolo[5,1-a]isoquinoline,2-(beta-methoxyethyl)-s-triazolo[5,1-a]isoquinoline,Z-ethoxymethyl-s-triazolo [5,1-a1isoquinoline,2-(2-pyridyl)-s-triazolo[5,1-a1isoquinoline,

and the like.

Another way to prepare substituted s-triazolo[5,1-a] isoquinolinederivatives is to react a readily obtainablestriazolo[5,1-a]isoquinoline (such as one containing one or more chlorosubstituents) in accordance with known reactions in order to introduceother substituent groups. The following reactions, where R represents ans-triazolo[5,1- a]isoquinolyl group, are illustrative:

NaOH RB: ROH or RONa (2) 301+ NaOR' ROR Among thes-triazole[5,1-a]isoquinolines that can be produced by theabove-exemplified reactions (i) through (2) are the following specificillustrative compounds:

Z-trifiuoromethyl-9-bromo-s-triazolo [5,1-a1isoquinoline,

2-methyl-5- (Z-dimethylaminoethoxy) -s-triazolo [5,1-a]

isoquinoline,

2-methyl-9-cyano-s-triazolo [5, l-a] isoquinoline,

Z-trifiuoromethyl-6-thiocyano-s-triazol0 [5, l-a] isoquinoline,

2-rnethyl-8,9-dichloro-s-triazolo [5 l -a] isoquinoline,

2,5 -dimethyl-6-aminomethyl-s-triazolo 5 l-a] isoquinoline,

2-phenyl-7-nitro-s-triazolo[5,1-a]isoquinoline,

Z-trifl-uoromethyl-6-ethylthio-s-triazolo[5,1-a]

isoquinoline,

and the like.

As is apparent from the foregoing discussion, a wide variety ofs-triazolo[5,l-a]isoquinolines are within the scope of the invention.For instance, the compounds that are within the invention can beillustrated by Formula II:

1& in

wherein R represents alkyl, alkaryl, aralkyl, aryl, halo alkyl,cycloalkyl, heterocyclic groups (particularly 5- or 6- membered ringscontaining oxygen or nitrogen as the hetero atom), and alkoxyalkyl.Usually, the R variable will contain not more than 20, and preferably,not more than 10, carbon atoms. The most preferred R variables are loweralkyl (i.e., C -C alkyl) and especially methyl, trifiuoromethyl, andphenyl. The R R R R R and p R variables individually can be hydrogen,alkyl, alkoxy,

halo, nitro, cyano, amino, dialkylamino, aminoalkylamino,dialkylaminoalkylamino, hydroxyl, dialkylaminoalkoxy, thiocyano,aminoalkyl and alkylthio. Usually the substituent group will contain notmore than 20 carbon atoms, and preferably not more than 8 carbon atoms.Preferred su-bstituent groups include bromo, chloro, lower alkoxy andlower alkyl (i.e., C -C alkoxy and alkyl) especially methoxy, methyl andethyl, cyano, amino, dimethylamino, diethylamino, 2-arninoethylamino,3-arninopropylamino, 2 dimethylaminoethylamino, 3 dimethylaminopropylamino, Z-diethylaminoethoxy, aminomethyl, C -C alkylthio and hydrogen.

A second class of compositions that are provided by the invention arethe 5,6-dihydro s triazolo[5,l a]isoquinolines such as those that arerepresented by Formula III:

wherein R R R R", R R and R are as defined in Formula II, above. The5,6-dihydro-s-triazolo[5,1-a]isoquinolines of the invention can beproduced by hydrogenation, under conditions described below, of thecorresponding s-triazolo[5,1-a]isoquinoline, or by hydrogenation of ans-triazolo[5,1-a]isoquinoline followed by the preparation of derivativesby known reactions such as reactions (i) through (2), above.

The hydrogenation reaction can be conveniently carried out in accordancewith the following procedure:

The s-triazolo[5,1-a]isoquinoline to be hydrogenated is charged to aconventional pressure vessel, such as an autoclave, along with an inertsolvent such as ethanol or isopropanol. A catalytic quantity of ahydrogenation catalyst is then added. Useful catalysts include nickel,palladium or platinum deposited on charcoal, with palladium on charcoalbeing preferred. Useful catalytic quantities for 1 mole ofs-triazolo[5,l-a]isoquinoline have been found to be from about 20 to 40grams of a catalyst consisting of about 5 weight percent nickel,palladium or platinum on charcoal. (The weight refers to active metalcatalyst plus charcoal, not to active metal catalyst alone.) 5 Theautoclave is then flushed with hydrogen, sealed, and hydrogen gas isinjected to a pressure of, for example, over 20 atmospheres and up to100 atmospheres or more. The autoclave is shaken to saturate themixture, and additional hydrogen is added to bring the pressure back up.The autoclave is then slowly heated from room temperature at a rate of,for example, about 20 C. per hour, and the pressure increase is plottedagainst time (or temperature). Before the reaction starts, the graph ofpressure vs. time or temperature will be very close to linear. Theinitiation of the hydrogenation reaction is detected by a somewhat lowerrise than that extrapolated. When the reaction starts, heating isreduced and the temperature is allowed to increase by about C. and it isthere stabilized. At this temperature, the hydrogenation reaction ratewill be about 0.01 mole per hour per gram of catalyst (catalyst refersto active metal plus charcoal). Reaction rates would increase by afactor of 2 for a 10 C. rise in temperature.

The hydrogenation reaction is normally carried out at temperatureswithin the range of from about 50 to 160 C., and preferably from about90 to 110 C. The reaction is followed by observing the pressuredecrease. When the pressure stops decreasing, the reaction has stopped.

Under the conditions described above, the hydrogenation is selective forthe 5,6-position. Additional hydrogenation on the rings does not becomesignificant until the temperature is increased about 50 C. above thetemperature at which reaction is first observed.

The hydrogenated product is recovered by standard procedures such as byfiltration to separate the catalyst, evaporation of the solvent, andrecrystallization from a convenient solvent such as ethanol, butanol,cyclohexane, benzene, ethanol/water, or the like. Yields are usually 80percent or higher.

Among the 5,6-dihydro-s-triazolo[5,1-a]isoquinolines that are within theinvention are the following specific illustrative compounds:

2-methyl-5 ,6-dihydro-s-triazolo [5 l-a] isoquinoline,

2-trifluoromethyl-5,6-dihydro-s-triazolo [5,1-a] isoquinoline,

2-phenyl-5,6-dihydro-s-triazolo [5,1-a]isoquinoline,

8,9-dimethoxy-2-methyl-5,6-dihydro-s-triazolo [5,1-

a] isoquinoline,

5-chloro-2-trifluoromethyl-5,6-dihydros-triazolo [5,1-

a] isoquinoline,

6-chloro-2-methyl-5,6-dihydro-s-triazolo[5,1-a]isoquinoline,

9-chloro-2-phenyl-5,6-dihydro-s-triazolo[5,1-a]is0- quinoline,

5 -methylthio-2-methyl-5 ,6-dihydro-s-triazolo [5 1- a] isoquinoline,

9- [2- (N,N-dimethylamino ethoxy] -2-methyl-5 ,6-

dihydro-s-triazolo [5 l-a] isoquinoline,

and the like.

The compounds of the invention are very useful. Because they are basicin nature, they can be used as hydrogen halide acceptors in processessuch as the one disclosed in US. Pat. No. 3,071,605 for the productionof cyclopentadienyl metal compounds. The compounds can be used ascorrosion inhibitors in aqueous ethylene glycolbased cooling liquids.The compounds of the invention that contain active hydrogen atoms can bereacted with ethylene oxide to form surface active agents useful aswetting agents, detergents, and the like. The compounds are also usefulas reaction intermediates.

The following examples illustrate the invention:

EXAMPLE 1 (a) N-(l-isoquinolyl)benzamidine 28.8 gramsl-aminoisoquinoline were dissolved in ml. methylnaphthalene and 20.6grams benzonitrile were added. The mixture was stirred and heated to 180C. At this temperature, 28 grams aluminum chloride were added slowly.The reaction is exothermic. After having stirred the mixture at 180190C. during another 2 hours, it was cooled down to room temperature andpoured into 500 ml. water containing 50 ml. concen trated hydrochloricacid. The methylnaphthalene was decanted and the aqueous solution wasextracted with benzene to remove the last traces of methylnaphthalene.The aqueous solution was then cooled to 0 C. and added slowly to asolution of 2 N-KOH until the precipitation was complete. It wasextracted with diethylether and the dry etheral solution was evaporatedand the residue dissolved in benzene. The benzene solution was passedthrough an aluminum oxide column and eluted with benzene. The desiredamidine is in the benzene solution whereas the unreacted amine remainson the column.

The amidine was obtained by evaporation of the benzene and crystallizedin cyclohexane. Yield: 44%, M.P. C.

Elemental analysis.Calcd. (percent): C, 77.71; H, 5.30; N, 16.99. Found(percent): C, 77.81; H, 5.32; N, 16.69.

(b) Z-phenyI-s-triazolo[5,1-a]isoquinoline 0.7 gram ofN-(l-isoquinolyl)benzamidine was dissolved in 25 ml. benzene and 1.7grams lead tetraacetate containing 45% acetic acid were added to thesolution. The mixture was refluxed for 30 minutes with stirring and thencooled down to room temperature. The precipitate was filtered, washedwith benzene and the filtrate was washed with an aqueous solution of 30%NaOH. The benzene layer was dried and evaporated, and the residue wascrystallized in cyclohexane. Yield: 0.55 g. (79%), M.P. 159-l61 C.

Elemental analysis.Calcd. (percent): C, 78.33; H, 4.52; N, 17.13. Found(percent): C, 78.42; H, 4.49; N, 17.33.

EXAMPLE 2 (a) N-( l-isoquinolyl)methylamidine 28.8 gramsl-aminoisoquinoline were dissolved in 400 ml. benzene and 25 gramsacetonitrile and 50 grams AlCl; were added to the solution in anautoclave. The mixture was heated at -190 C. for 2.5 hours. Aftercooling down to room temperature, the reaction mixture was poured into500 ml. water containing 50 ml. concentrated HCl and the benzene wasdecanted, the aqueous solution cooled down to 0 C., and 2 N-KOH addeduntil precipitation was complete. The crude amidine was dissolved indiethyl ether and the dried ethereal solution evaporated. The residuewas dissolved in benzene and the benzene solution passed through aneutral aluminum oxide column. The amidine was eluted with benzene andthe benzene solution evaporated. The residue was crystallized incyclohexene. M.P. 128130 C. Yield 35%.

Elemental analysis.Calcd. (percent): C, 71.33; H, 5.99; N, 22.69. Found(percent): C, 71.22; H, 5.98; N, 23.01.

(b) Z-methyl-s-triazolo[5,1-a]isoquino1ine This compound was preparedapplying the same procedure described in Example 1(b).

From 5.55 grams amidine 4.9 grams (89%) of the desired title compoundwere obtained. M.P. 88-89 C.

Elemental analysis.-Calcd. (percent): C, 72.11; H, 9.95; N, 22.94. Found(percent): C, 72.68; H, 5.22; N, 22.43.

1 1 EXAMPLE 3 (a) N-( l-isoquinolyl trifiuoromethylamidine In contrastto the preparations of N-(l-isoquinolyl) alkylor aryl-amidines, in thecase of trifluoroacetonitrile, no catalyst is needed. The reaction ofthe nitrile with the amine takes place at room temperature.

14.4 grams l-aminoisoquinoline were dissolved in 200 ml. acetonitrileand 15 grams gaseous trifluoroacetonitrile were introduced slowly withstirring. After 65 hours standing at room temperature the solvent wasevaporated and the residue was crystallized in a small quantity ofcyclohexene. M.P. 5859* C. Yield 72.5%.

Elemental analysis.-Calcd. (percent): C, 55.23; H, 3.37; N, 17.57. Found(percent): C, 56.11; H, 3.60; N, 17.18.

(b) Z-trifiuoromethyl-s-triazolo l-a] isoquinoline The procedure isanalogous to Example 1(b), using the product of Example 3(a). Thereaction time is, however, only 20 minutes. Yield: 40%. M.P. 130-132 C.

Elemental analysis.--Calcd. (percent): C, 55.69; H, 2.55; N, 17.72.Found (percent): C, 55.40; H, 2.74; N, 16.89.

EXAMPLE 4 To a 250 ml. autoclave were charged 0.05 mole2-methyl-s-triazolo[5,1-a]isoquinoline, 100 milliliters of isopropanol,and 1.5 gram of 5 weight percent palladium on charcoal (Type 16, fromJohnson Mabbluy and Company). The autoclave was flushed with hydrogen,sealed and filled with hydrogen at room temperature to about 88kilograms per cm. pressure. The autoclave was slowly heated to 90 C. andheld there until the hydrogen pres- 12 sure levelled 01f. Reaction rateat 90 C. was M mole/ hour/gram of catalyst. The autoclave was cooled andvented, and the solvent was evaporated. After recrystallization frombenzene/cyclohexane, there was obtained 2-methyl-5,6-dihydr0-s-triazolo[5,1-a] isoquinoline. M.P. 54-56 C. in 80 percent yield.

Elemental analysis.Calcd. (percent): C, 71.33; H, 5.99; N, 22.69. Found(percent): C, 71.44; H, 6.12; N, 22.83.

What is claimed is:

1. The compound 2-methy-l 5,6 dihydro s triazolo [5,1-a]isoquinoline.

References Cited UNITED STATES PATENTS 3,206,468 9/1965 Grenda 260288 X3,388,130 6/1968 Pesson 260288 X 3,639,406 2/ 1972 Reimlinger 2602883,663,551 5/1972 Deryckere 260288 OTHER REFERENCES Nair et al.:Abstracted in Chem. Abstr. vol. 68, col. 105102(s) (1968).

Na-qui et al.: Abstracted in Chem. Abstr. vol. 63, col. 8345 (1965).

DONALD G. DAUS, Primary Examiner U.S. Cl. X.R.

200 2s3 CN, 289 'R, 28 6 R; 2 -2949, 326.62, 346.1 R, 464, 465 R, 465.1,465.7

